Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas.

中文翻译：

---

蛋白质 neddylation 作为肺和肺外小细胞癌的治疗靶点

小细胞肺癌 (SCLC) 是所有实体瘤恶性肿瘤中最致命的一种。为了确定这种顽固性癌症类型的新治疗方法，我们将基因组规模的 CRISPR/Cas9 灭活筛选应用于我们从 SCLC 小鼠模型中获得的细胞系。SCLC 细胞对 NEDD8 和其他 neddylation 途径基因的缺失特别敏感。使用 MLN4924 对该途径的遗传抑制或药理学抑制不仅在小鼠 SCLC 细胞系中，而且在体外或体内治疗的肺和肺外小细胞癌的患者衍生异种移植 (PDX) 模型中导致细胞死亡。PDX 模型的一个子集对 neddylation 抑制异常敏感。Neddylation 抑制抑制神经内分泌细胞状态的主要调节因子如 INSM1 和 ASCL1 的表达，SCLC 的一个子集依赖于细胞增殖和存活。为了确定对 neddylation 抑制的潜在耐药机制，我们进行了基因组规模的 CRISPR/Cas9 抑制筛选。删除 COP9 信号体的成分大大减轻了 neddylation 抑制在小细胞癌中的作用，包括 MLN4924 抑制神经内分泌转录程序表达的能力。这项工作将 neddylation 确定为神经内分泌细胞状态的调节剂和小细胞癌的潜在治疗靶点。删除 COP9 信号体的成分大大减轻了 neddylation 抑制在小细胞癌中的作用，包括 MLN4924 抑制神经内分泌转录程序表达的能力。这项工作将 neddylation 确定为神经内分泌细胞状态的调节剂和小细胞癌的潜在治疗靶点。删除 COP9 信号体的成分大大减轻了 neddylation 抑制在小细胞癌中的作用，包括 MLN4924 抑制神经内分泌转录程序表达的能力。这项工作将 neddylation 确定为神经内分泌细胞状态的调节剂和小细胞癌的潜在治疗靶点。